1. Field of the Invention
The present invention provides new methods for preparation of various oxygen ring compounds (oxygen as an alicyclic ring member) including 2,5-disubstituted-tetrahydrofurans, 2,6-disubstituted tetrahydropyrans, 2,7-disubstituted oxepanes and 2,8-oxocanes. The invention further provides novel compounds and pharmaceutical compositions and therapeutic methods that comprise such compounds.
2. Background
Leukotrienes are recognized potent local mediators, playing a significant role in inflammatory and allegeric responses, including arthritis, asthma, psoriasis and thrombotic disease. Leukotrienes are produced by the oxidation of arachidonic acid by lipoxygenase. More particularly, arachidonic acid is oxidized by 5-lipooxygenase to the hydroperoxide 5-hydroperoxy-eicosatetraenoic acid (5-HPETE), that is converted to leukotriene A4, that in turn can be converted to leukotriene B4, C4, or D4. The slow-reacting substance of anaphylaxis is now known to be a mixture of leukotrienes C4, D4 and E4, all of which are potent bronchoconstrictors.
Efforts have been made to identify receptor antagonists or inhibitors of leukotriene biosynthesis, to prevent or minimize pathogenic inflammatory responses mediated by leukotrienes.
For example, European Patent Application Nos. 901171171.0 and 901170171.0 report indole, benzofuran, and benzothiophene lipoxygenase inhibiting compounds.
Various 2,5-disubstituted tetrahydrofurans have exhibited significant biological activity, including as lipoxygenase inhibitors. See U.S. Pat. Nos. 5,703,093; 5,681,966; 5,648,486; 5,434,151; and 5,358,938.
While such compounds are highly useful therapeutic agents, current methods for synthesis of least some of the compounds require lengthy routes, and reagents and protocols that are less preferred in larger scale operations, such as to produce kilogram quantities.
It thus would be desirable to have improved methods to substituted tetrahydrofurans and other cyclic oxygen compounds, particularly new syntheses that facilitate larger scale production of such compounds.
We have now found new methods for preparation of cyclic oxygen compounds, including 2,5-disubstituted tetrahydrofurans, 2,6-disubstituted tetrahydropyrans, 2,7-disubstituted oxepanes and 2,8-oxocanes. These methods utilize reagents and synthetic protocols that facilitate large scale manufacture, and provide increased yields relative to prior approaches.
The methods of the invention are suitable for preparation of a variety of cyclic oxygen-containing compounds (i.e., alicyclic compounds having an oxygen ring member), including compounds of the following Formula I: 
wherein Ar is optionally substituted carbocyclic aryl or optionally substituted heteroaryl;
each R1, X and Y is independently hydrogen or a non-hydrogen substituent such as halogen, hydroxyl, optionally substituted alkyl preferably having from 1 to about 20 carbon atoms, optionally substituted alkenyl preferably having from 2 to about 20 carbon atoms, optionally substituted alkynyl preferably having from 2 to about 20 carbon atoms, optionally substituted alkoxy preferably having from 1 to about 20 carbon atoms, optionally substituted alkylthio preferably having from 1 to about 20 carbon atoms, optionally substituted alkylsulfinyl preferably having from 1 to about 20 carbon atoms, optionally substituted alkylsulfonyl preferably having from 1 to about 20 carbon atoms, optionally substituted aminoalkyl preferably having from 1 to about 20 carbon atoms, optionally substituted alkanoyl preferably having from 1 to about 20 carbon atoms, optionally substituted carbocyclic aryl having at least about 6 ring carbons, or substituted or unsubstituted aralkyl having at least about 6 ring carbons, and the like;
Z is a chemical bond, optionally substituted alkylene, optionally substituted alkenylene, optionally substituted alkylene, optionally substituted heteroalkylene, optionally substituted heteroalkenylene, optionally substituted heteroalkylene, or a hetero atom such as O, S, S(O), S(O)2, or NR1 wherein R1 is the same as defined immediately above;
n is an integer from 1 to 11, and preferably is 1 to 9, more preferably 1 to 7;
p is an integer from 0 (where the xcex1 and xcex2 ring positions are fully hydrogen-substituted) to 4; and pharmaceutically acceptable salts thereof.
The methods of the invention are particularly suitable for synthesis of substituted tetrahydrofurans, including compounds of the following Formula II: 
wherein Ar is optionally substituted aryl or heteroaryl;
m is 0 or 1; n is 1-6;
W is xe2x80x94AN(OM)C(O)N(R3)R4, xe2x80x94N(OM)C(O)N(R3)R4, xe2x80x94AN(R3)C(O)N(OM)R4, xe2x80x94N(R3)C(O)N(OM)R4, xe2x80x94AN(OM)C(O)R4, xe2x80x94N(OM)C(O)R4, xe2x80x94AC(O)N(OM)R4, xe2x80x94C(O)N(OM)R4, or xe2x80x94C(O)NHA; and A is lower alkyl, lower alkenyl, lower alkynyl, alkylaryl or arylalkyl, wherein one or more carbons optionally can be replaced by N, O or S, however xe2x80x94Yxe2x80x94Axe2x80x94, xe2x80x94Axe2x80x94, or xe2x80x94AWxe2x80x94 should not include two adjacent heteroatoms;
M is hydrogen, a pharmaceutically acceptable cation or a metabolically cleavable leaving group;
X and Y are each independently O, S, S(O), S(O)2, NR3 or CHR5;
Z is O, S, S(O), S(O)2, or NR3;
R1 and R2 are each independently hydrogen, lower alkyl, C3-8 cycloalkyl, halolower alkyl, halo or xe2x80x94COOH;
R3 and R4 are independently hydrogen, alkyl, alkenyl, alkynyl, aryl, arylalkyl, C1-6alkoxy-C1-10alkyl, C1-6 alkylthio-C1-10 alkyl, heteroaryl, or heteroarylalkyl;
R5 is hydrogen, lower alkyl, lower alkenyl, lower alkynyl, arylalkyl, alkaryl, xe2x80x94AN(OM)C(O)N(R3)R4, xe2x80x94AN(R3)C(O)N(OM)R4, xe2x80x94AN(OM)C(O)R4, xe2x80x94AC(O)N(OM)R4, xe2x80x94AS(O)xR3, xe2x80x94AS(O)xCH2C(O)R3, xe2x80x94AS(O)xCH2CH(OH)R3, or xe2x80x94AC(O)NHR3, wherein x is 0-2; and pharmaceutically acceptable of such compounds.
Compounds of Formula II have been disclosed in U.S. Pat. No. 5,703,093. As disclosed in that patent, preferred compounds of Formula II include compounds where Ar is substituted by halo (including but not limited to fluoro), lower alkoxy (including methoxy), lower aryloxy (including phenoxy), W (as defined above in Formula II), cyano, or R3 (as defined above in Formula II). Those substituents are also preferred Ar group substituents for compounds of other formulae disclosed herein. Specifically suitable Ar groups for the above Formula II as well as the other formulae disclosed herein include phenyl, trimethoxyphenyl, dimethoxyphenyl, fluorophenyl (specifically 4-fluorophenyl), difluorophenyl, pyridyl, dimethoxypyridyl, quinolinyl, furyl, imidazolyl, and thienyl. Additionally, in Formula II as well as other formulae disclosed herein, W suitably is lower alkyl, such as a branched alkyl group, e.g. xe2x80x94(CH2)nC(alkyl)Hxe2x80x94, wherein n is 1-5, and specifically xe2x80x94(CH2)2C(CH3)Hxe2x80x94, or lower alkynyl such as of the formula xe2x80x94Cxe2x89xa1Cxe2x80x94CH(alkyl)-, including xe2x80x94Cxe2x89xa1Cxe2x80x94CH(CH3)xe2x80x94.
In particularly preferred aspect, methods of the invention are employed to synthesis the following compound 1, 2S,5S-trans-2-(4-fluorophenoxymethyl)-5-(4-N-hydroxyureidyl-1-butynyl)-tetrahydrofuran: 
It has been found that biological activity, particularly 5-lipoxygenase activity, can vary among optically active isomers of compounds of the invention, and therefore a single optical isomer of a compound may be preferred. Accordingly, the synthetic methods of the invention include preparation of enantiomerically enriched compounds of the invention.
In a first preferred aspect, substituted tetrahydrofuran compounds are provided by reacting a hydroxy substituted aryl compound with an epoxide having a reactive carbon, e.g. a glycidyl compound substituted at the C3 position with an electron-withdrawing group such as halo (e.g. epichlorohydrin, epibromohydrin), mesyl or tosyl (glycidyl mesylate and glycidyl tosylate), etc., to form an epoxyarylether or epoxyoarylether in the presence of base and preferably at or above about 0xc2x0 C. (As used herein, the term xe2x80x9carylxe2x80x9d refers to both carbocyclic aryl and heteroaromatic or heteroaryl groups, which terms are further discussed below). That epoxyether is then reacted with an active methylene compound to form a lactone, preferably a xcex3-lactone. The active methylene compound can be a variety of agents. Diethyl and dimethyl malonate are generally preferred, which provide an ethyl or methyl ester as a lactone ring substituent. That ester group is then removed (e.g. via hydrolysis and decarboxylation), and the lactone suitably reduced to a hydroxy-substituted tetrahydrofuran, particularly a hydroxytetrahydrofuran-aryl ether.
The hydroxy tetrahydrofuran can be further functionalized as desired, particularly by activating the hydroxyl substituent of the hydroxytetrahydrofuran-aryl ether followed by substitution of the corresponding position of the tetrahydrofuran ring such as by a 1-alkyne reagent. Also, rather than directly activating the hydroxyl moiety, that group can be replaced with a halide, and the halide-substituted tetrahydrofuran reacted with a benzylsulfonic acid reagent.
It also has been found that methods of the invention enable such substitution of the tetrahydrofuran to proceed with extremely high stereoselectivity, e.g. at least greater than about 60 mole percent of one stereoisomer than the other, more typcially greater than about 70 or 75 mole percent of one stereoisomer than the other isomer. Recrystallization of such an enantiomerically enriched mixture has provided very high optical purities, e.g. about 95 mole %, 97 mole % or even 99 mole % or more of the single stereoisomer.
In another aspect, methods are provided that involve cleavage of a bis-compound to provide high yields of tetrahydrofuran compounds, including compounds of Formula II above. These methods preferably involve condensation of mannitol with an alkanoyl compound such as formaldehyde to form a trialkylene mannitol such as a tri(C1-10alkylene) mannitol such as trimethylene mannitol where formaldehyde is employed, which is then cleaved to form 2,5,-O-methylene-mannitol, which has two primary hydroxyl groups and two secondary hydroxyl groups. The primary hydroxyl groups are protected (e.g. as esters) and the secondary hydroxyl groups then are suitably cyclized, e.g. with a trialkylorthoformate reagent, to provide a cyclic ether. The protected primary alcohols are then converted to aryl ethers, followed by cleavage of the cyclic ether to provide again the secondary hydroxyl groups. The mannitol compound then undergoes oxidative cleavage to provide the corresponding alicyclic dialdehyde, which aldehyde groups are functionalized to bis-xcex1,xcex2-unsaturated esters. The carbon-carbon double bonds of that compound are suitably saturated, and the bis-compound cleaved and the cleavage products cyclized to provide an aryltetrahydrofuran ether which can be further functionalized as described above.
In yet another aspect of the invention, preparative methods are provided that include multiple reactions that surprisingly proceed as a single step without isolation of intermediates to provide oxygen ring compounds that have varying ring size as desired. These methods are suitable for preparation of oxygen ring compounds having from 5 to 12 or more ring members, and are particularly useful for synthesis of oxygen ring compounds having from 5 to 8 or 9 ring members.
Moreover, it has been surprisingly found that the one step procedure is enantioselective. Hence, if the starting reagent (a 2,3-epoxide) is optically active, the resulting substituted oxygen ring compound also will be optically active. Moreover, the reaction proceeds with stereoselectivity, i.e. full rentention of configuration.
More particularly, in this aspect of the invention the methods include formation, in a single step, of an alkynyl-substituted oxygen ring compound. For preparation of an alkynyl-tetrahydrofuran, a compound is reacted that has at least a six-carbon alkyl or alklyene chain that is activated at the 1- and 6-carbon positions such as by substitution by suitable leaving groups, and 2- and 3-carbon positions of the chain form an epoxide ring. The leaving groups of the 1- and 6-positions may be e.g. halo, such as chloro or bromo, or an ester, such as an alkyl or aryl sulfonic ester. Preferably, the 1-position is halo-substituted, particularly bromo-, iodo- or chloro-substituted, and the 6-position is substituted by an ester such as by a benzylsulfonyl group. That compound is reacted with a molar excess of a strong base such as an alkyllithium reagent that affords an alkynyl-substituted tetrahydrofuran in a single step.
Larger ring alkynyl-substituted compounds are readily provided through corresponding chain homologation of the epoxy reagent, i.e. by interposing additional xe2x80x9cspacingxe2x80x9d or alkylene chain members between the reagent""s activated positions.
Thus, for example, to prepare an alkynyl-substituted tetrahydopyran, a reagent is employed that has at least a seven-carbon alkyl or alkylene chain that is activated at the 1- and 7-carbon positions e.g. by substitution by suitable leaving groups (such as those mentioned above), and the 2- and 3-positions of the chain form an epoxide ring. That compound is reacted with base to provide an alkynyl-substituted tetrahydropyran.
Similarly, to prepare an alkynyl-substituted oxepane, a reagent is employed that has at least a seven-carbon alkyl or alkylene chain activated (particularly by leaving groups) at the 1- and 8-carbon positions, and the 2- and 3-postion of the chain form an epoxide ring. To prepare an alkynyl-substituted oxocane compound, a reagent is employed that has at least eight-carbon alkyl of alkylene chain activated at the 1- and 9-carbon positions, with the 2- and 3-positions of the chain forming an epoxide ring. Treatment of those respective reagents with appropriate base provides alkynyl-substituted oxepane and oxocane compounds.
In another aspect of the invention, a chiral synthon is preferably employed such as glyceraldehyde, mannitol, ascorbic acid, and the like, that can provide stereoselective routes to desired compounds of the invention. This approach includes formation of a substituted dioxolane, typically a 1,3-dioxolane (particularly (2,2-dimethyl)-1,3-dioxolane), which preferably is optically active. A side chain of the dioxolane, preferably at the 4-position, is suitably extended e.g. by one or more Wittig reactions, typically one, two or more Wittig reactions that provide xcex1,xcex2-unsaturated moieties such as an xcex1,xcex2-unsaturated C1-6alkyl ester. Such an xcex1,xcex2-unsaturated provided then can be epoxidized, preferably by asymmetric oxidation of the conjugated alkene to provide an optically active epoxide, which then participates in an elimination reaction to yield a propargyl alcohol as the dioxolane ring substituent. The dioxolane ring then can be opened, typically in the presence of acid and the acyclic intermediate cyclized to provide an optically active oxygen alicyclic compound. See Scheme XV below and the discussion related thereto below. The substituted alicyclic compound can be further functionalized as desired. For instance, the primary hydroxy of the alkylhydroxy substituent of the cyclic compound can be esterified (e.g., sulfonate such as a tosylate) and the activated methyl reacted to provide an aryl substituent, e.g. optionally substituted phenyl substituent. The alkynyl substituent can be extended to provided the hydroxy urea as discussed herein.
In yet a further aspect of the invention, an alkyne-substituted tetrahydrofuran is prepared directly (e.g., without a dioxolane intermediate) from an acyclic keto alkyne compound. More specifically, a keto alkynyl reagent with terminal alkenyl group is suitably employed, e.g. xe2x80x94CH2xe2x95x90CH(CH2)nC(xe2x95x90O)Cxe2x89xa1CR where n is an integer of 2 to 6, preferably 2 to 5, and R is suitably C1-6 alkyl and the like. The terminal alkene is then epoxidized, e.g. by ozonolysis or other suitable oxidant. The epoxidized keto alkyne then can be cyclized, e.g. in the presence of boron methyl sulfide and the resulting oxygen alicyclic compound functionalized as desired.
Further provided are new routes to substituted hydroxy ureas. In preferred aspects, these routes include reaction of a protected hydroxyurea (e.g., a compound of the formula NH2C(O)NHOR, where R is a hydroxy protecting group such as para-methoxybenzyl-) with a substituted alcohol in the presence of suitable dehydrating agent(s) to provide an amino ester, which is treated with ammonia and a Lewis acid to provide a hydroxy urea.
As mentioned above, compounds produced by the methods of the invention are useful as pharmaceutical agents, particularly to treat disorders or diseases mediated by 5-lipoxygenase such as immune, allegeric and cardiovascular disorders and diseases, e.g. general inflammation, hypertension, skeletal-muscular disorders, osteoarthritis, gout, asthma, lung edema, adult respiratory distress syndrome, pain, aggregation of platelets, shock, shock, rheumatoid arthritis, psoriatic arthritis, psoriasis, autoimmune uveitis, allergic encephalomyelitis, systemic lupus erythematosis, acute necrotizing hemmorrhagic encephalopathy, idiopathic thrombocytopenia, polychondritis, chronic active hepatitis, idiopathic sprue, Crohn""s disease, Graves ophthalmopathy, primary biliary cirrhosis, uveitis posterior, interstitial lung fibrosis, allergic asthma and inappropriate allergic responses to environmental stimuli.
In other aspects, the invention provides new compounds as well as pharmaceutical compositions that comprise one or more of such compounds preferably with a pharmaceutically acceptable carrier. More particularly, the invention in a composition aspect includes compounds of Formula I above, where n is 2 or greater (i.e. compounds with alicyclic oxygen rings that have 6 or more ring members), which includes compounds of Formulae III, IIIa, IV, IVa, V, Va, as those formulae are defined below. The invention further provides methods for treatment and/or prophylaxis of various disorders and diseases including those disclosed above such as immune, allegeric and cardiovascular disorders and diseases, the methods in general comprising administering an effective amount of one or more compounds of Formula I above, where n is 2 or greater, to a subject, such as a mammal particularly a primate such as a human, that is suffering from or susceptible to such a disorder or disease.
Compounds produced by the methods of the invention are useful as synthetic intermediates to prepare other compounds that will be useful for therapeutic applications. Other aspects of the invention are disclosed infra.
As discussed above, the invention provides methods that are particularly suitable for synthesis of compounds of the following Formula I: 
wherein Ar, Z, X, Y, R1, n and p are as defined above.
As discussed above, in addition to the above-discussed substituted tetrahydrofurans, methods of the invention also provide oxygen ring compounds having 6 or more ring members.
More particularly, preferred compounds produced by the methods of the invention include substituted tetrahydropyrans, including substituted tetrahydropyrans of the following Formula III: 
wherein Ar, Z and R1 are each the same as defined above for Formula I, and q is an integer of from 0 to 9, and preferably q is 1, 2, 3 or 4; and pharmaceutically acceptable salts thereof.
Generally preferred are 2,6-disubstituted tetrahydropyrans, such as compounds of the following Formula IIIa: 
wherein Ar, Z, Y, W, R1 and m are each the same as defined for Formula II above, and qxe2x80x2 is an integer of from 0 to 6, and preferably qxe2x80x2 is 0, 1, 2, 3 or 4; and pharmaceutically acceptable salts thereof.
The methods are also particularly useful for preparations of substituted oxepanes including compounds of the following Formula IV: 
wherein Ar, Z and R1 are each the same as defined above for Formula I, and r is an integer of from 0 to 11, and preferably r is 1, 2, 3 or 4; and pharmaceutically acceptable salts thereof.
Generally preferred are 2,7-disubstituted oxepanes, such as compounds of the following Formula IVa: 
wherein Ar, Z, Y, W, R1 and m are each the same as defined for Formula II above, and rxe2x80x2 is an integer of from 0 to 10, and preferably rxe2x80x2 is 0, 1, 2, 3 or 4; and pharmaceutically acceptable salts thereof.
Still further, methods of the invention can be especially useful for synthesis of substituted oxocanes, such as compounds of the following Formula V: 
wherein Ar, Z and R1 are each the same as defined above for Formula I, and s is n integer of from 0 to 13, and preferably s is 1, 2, 3 or 4; and pharmaceutically acceptable salts thereof.
Generally preferred are 2,8-disubstituted oxocanes, such as compounds of the following Formula Va: 
wherein Ar, Z, Y, W, R1 and m are each the same as defined for Formula II above, and sxe2x80x2 is an integer of from 0 to 10, and preferably sxe2x80x2 is 0, 1, 2, 3 or 4; and pharmaceutically acceptable salts thereof.
Preferred compounds of the invention include those having one or more hydroxy and/or alkoxy substituents on the alicyclic ring, typically one, two or three hydroxy and/or alkoxy ring substituents. Hence, in the above formulae I, III, IIIa, IV, IVa, V, IVa, each R1 is independently hydroxy or alkoxy and p is one or greater. Typical alkoxy alicyclic ring substituents include C1-8alkoxy, more typically C1-6alkoxy, still more typically C1-3alkoxy compounds. Particularly preferred compounds include those where at least two hydroxy and/or alkoxy groups are substituents on adjacent carbons of the alicyclic ring, e.g. vicinal di-hydroxy compounds and vicinal di-alkoxy compounds.
The term alkyl, as used herein, unless otherwise specified, refers to a saturated straight, branched, or cyclic hydrocarbon and unless otherwise specified is C1 to C10, and specifically includes methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, cyclopentyl, isopentyl, neopentyl, hexyl, isohexyl, cyclohexyl, 3-methylpentyl, 2,2-dimethylbutyl, and 2,3-dimethylbutyl. The alkyl group can be optionally substituted with any appropriate group, including but not limited to R3 or one or more moieties selected from the group consisting of halo, hydroxyl, amino, alkylamino, arylamino, alkoxy, aryloxy, nitro, cyano, sulfonic acid, sulfate, phosphonic acid, phosphate, or phosphonate, either unprotected, or protected as necessary, as known to those skilled in the art, for example, as disclosed in Greene et al., xe2x80x9cProtective Groups in Organic Synthesisxe2x80x9d, John Wiley and Sons, Second Edition, 1991.
The term halo, as used herein, refers to chloro, fluoro, iodo, or bromo.
The term lower alkyl, as used herein, and unless otherwise specified, refers to a C1 to C6 saturated straight, branched, or cyclic (in the case of C5-6) hydrocarbon, and specifically includes methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, cyclopentyl, isopentyl, neopentyl, hexyl, isohexyl, cyclohexyl, 3-methylpentyl, 2,2-dimethylbutyl, and 2,3-dimethylbutyl, optionally substituted as described above for the alkyl groups.
The term alkenyl, as referred to herein, and unless otherwise specified, refers to a straight, branched, or cyclic (in the case of C5-6) hydrocarbon of C2 to C10 with at least one double bond, optionally substituted as described above.
The term lower alkenyl, as referred to herein, and unless otherwise specified, refers to an alkenyl group of C2 to C6, and specifically includes vinyl and allyl.
The term lower alkylamino refers to an amino group that has one or two lower alkyl substituents.
The term alkynyl, as referred to herein, and unless otherwise specified, refers to a C2 to C10 straight or branched hydrocarbon with at least one triple bond, optionally substituted as described above. The term lower alkynyl, as referred to herein, and unless otherwise specified, refers to a C2 to C6 alkynyl group, specifically including acetylenyl, propynyl, and xe2x80x94Cxe2x89xa1Cxe2x80x94CH(alkyl)xe2x80x94, including xe2x80x94Cxe2x89xa1Cxe2x80x94CH(CH3)xe2x80x94.
The term carbocyclic aryl, as used herein, and unless otherwise specified, refers to non-hetero aromatic groups that have 1 to 3 separate or fused rings and 6 to about 18 carbon rings members and may include e.g. phenyl, naphthyl, biphenyl, phenanthracyl, and the like. The carbocyclic aryl group can be optionally substituted with any suitable group, including but not limited to one or moieties selected from the group consisting of halo, hydroxyl, amino, alkylamino, arylamino, alkoxy, aryloxy, nitro, cyano, sulfonic acid, sulfate, phosphonic acid, phosphate, or phosphonate, either unprotected, or protected as necessary, as known to those skilled in the art, for example, as taught in Greene et al., xe2x80x9cProtective Groups in Organic Synthesisxe2x80x9d, John Wiley and Sons, Second Edition, 1991, and preferably with halo (including but not limited to fluoro), lower alkoxy (including methoxy), lower aryloxy (including phenoxy), W, cyano, or R3.
The term haloalkyl, haloalkenyl, or haloalkynyl refers to alkyl, alkenyl, or alkynyl group in which at least one of the hydrogens in the group has been replaced with a halogen atom.
The term heteroaryl, heterocycle or heteroaromatic, as used herein, refers to an aromatic moiety that includes at least one sulfur, oxygen, or nitrogen in the aromatic ring, which can optionally be substituted as described above for the aryl groups. Non-limiting examples are pyrryl, furyl, pyridyl, 1,2,4-thiadiazolyl, pyrimidyl, thienyl, isothiazolyl, imidazolyl, tetrazolyl, pyrazinyl, pyrimidyl, quinolyl, benzofuran, isoquinolyl, benzothienyl, isobenzofuryl, pyrazolyl, indolyl, purinyl, carbazolyl, benzimidazolyl, and isoxazolyl. Suitable heteroaromatic or heteroaryl groups will have 1 to 3 rings, 3 to 8 ring members in each ring and from 1 to 3 heteroatoms (N, O or S).
The term arylalkyl refers to a carbocyclic aryl group with an alkyl substituent.
The term alkylaryl refers to an alkyl group that has a carbocyclic aryl substituent.
The term organic or inorganic anion refers to an organic or inorganic moiety that carries a negative charge and can be used as the negative portion of a salt.
The term xe2x80x9cpharmaceutically acceptable cationxe2x80x9d refers to an organic or inorganic moiety that carries a positive charge and that can be administered in association with a pharmaceutical agent, for example, as a counter cation in a salt. Pharmaceutically acceptable cations are known to those of skill in the art, and include but are not limited to sodium, potassium, and quaternary amine.
The term xe2x80x9cmetabolically cleavable leaving groupxe2x80x9d refers to a moiety that can be cleaved in vivo from the molecule to which it is attached, and includes but it not limited to an organic or inorganic anion, a pharmaceutically acceptable cation, acryl (for example (alkyl)C(O), including acetyl, propionyl, and butyryl), alkyl, phosphate, sulfate and sulfonate.
Alkylene and heteroalkylene groups typically will have about 1 to about 8 atoms in the chain, more typically 1 to about 6 atoms in the linkage. Alkenylene, heteroalkenylene, alkynylene and heteroalkynylene groups typically will have about 2 to about 8 atoms in the chain, more typically 2 to about 6 atoms in the linkage, and one ore more unsaturated carbon-carbon bonds, typically one or two unsaturated carbon-carbon bonds. A heteroalkylene, heteroalkenylene or heteroalkynylene group will have at least one hetero atom (N, O or S) as a divalent chain member.
The term alkanoyl refers to groups that in general formulae generally will have from 1 to about 16 carbon atoms and at least one carbonyl (Cxe2x95x90O) moiety, more typically from 1 to about 8 carbon atoms, still more typically 1 to about 4-6 carbon atoms. The term alkylthio generally refers to moieties having one or more thioether linkages and preferably from 1 to about 12 carbon atoms, more preferably from 1 to about 6 carbon atoms. The term alkylsulfinyl generally refers to moieties having one or more sulfinyl (S(O)) linkages and preferably from 1 to about 12 carbon atoms, more preferably from 1 to about 6 carbon atoms. The term alkylsulfonyl generally refers to moieties having one or more sulfonyl (S(O)2) linkages and preferably from 1 to about 12 carbon atoms, more preferably from 1 to about 6 carbon atoms. The term aminoalkyl generally refers to groups having one or more N atoms and from 1 to about 12 carbon atoms, preferably from 1 to about 6 carbon atoms.
As discussed above, various substituent groups of the above formulae may be optionally substituted. Suitable groups that may be present on such a xe2x80x9csubstitutedxe2x80x9d group include e.g. halogen such as fluoro, chloro, bromo and iodo; cyano; hydroxyl; nitro; azido; sulfhydryl; alkanoyl e.g. C1-6 alkanoyl group such as acetyl and the like; carboxamido; alkyl groups including those groups having 1 to about 12 carbon atoms, preferably from 1 to about 6 carbon atoms; alkenyl and alkynyl groups including groups having one or more unsaturated linkages and from 2 to about 12 carbon atoms, preferably from 2 to about 6 carbon atoms; alkoxy groups having one or more oxygen linkages and from 1 to about 12 carbon atoms, preferably 1 to about 6 carbon atoms; aryloxy such as phenoxy; alkylthio groups including those moieties having one or more thioether linkages and from 1 to about 12 carbon atoms, preferably from 1 to about 6 carbon atoms; alkylsulfinyl groups including those moieties having one or more sulfinyl linkages and from 1 to about 12 carbon atoms, preferably from 1 to about 6 carbon atoms; alkylsulfonyl groups including those moieties having one or more sulfonyl linkages and from 1 to about 12 carbon atoms, preferably from 1 to about 6 carbon atoms; aminoalkyl groups such as groups having one or more N atoms and from 1 to about 12 carbon atoms, preferably from 1 to about 6 carbon atoms; carbocyclic aryl having 6 or more carbons, particularly phenyl; aryloxy such as phenoxy; aralkyl having 1 to 3 separate or fused rings and from 6 to about 18 carbon ring atoms, with benzyl being a preferred group; aralkoxy having 1 to 3 separate or fused rings and from 6 to about 18 carbon ring atoms, with O-benzyl being a preferred group; or a heteroaromatic or heteroalicyclic group having 1 to 3 separate or fused rings with 3 to about 8 members per ring and one or more N, O or S atoms, e.g. coumarinyl, quinolinyl, pyridyl, pyrazinyl, pyrimidyl, furyl, pyrrolyl, thienyl, thiazolyl, oxazolyl, imidazolyl, indolyl, benzofuranyl, benzothiazolyl, tetrahydrofuranyl, tetrahydropyranyl, piperidinyl, morpholino and pyrrolidinyl. A xe2x80x9csubstitutedxe2x80x9d group of a compound of the invention prepared by a method of the invention may be substituted at one or more available positions, typically 1 to about 3 positions, by one or more suitable groups such as those listed immediately above.
Particularly preferred preparative methods of the invention are exemplified in the following Schemes I through XVI. For purposes of exemplification only, particularly preferred compounds and substituents are depicted in the Schemes, and it will be understood that a variety of other compounds can be employed in similar manner as described below with respect to the exemplified compounds. For instance, the carbocyclic aryl group of 4-fluorophenol is depicted throughout the Schemes, although a wide variety of other aryl group could be employed in the same or similar manner as fluorophenyl. It should also be understood that references to xe2x80x9carylxe2x80x9d with respect to the Schemes and as otherwise specified herein includes those groups specified for the substituent Ar in Formula I above and thus encompasses carbocyclic aryl such as phenyl and the like as well as heteroaryl groups. Additionally, while compounds in the below Schemes generally depict substitution only at the ring carbons a to the ring oxygen, other ring positions can be readily substituted, e.g. by using appropriately substituted starting reagents. 
Scheme I exemplifies a preferred preparative method of the invention wherein arylhydroxide 2 is reacted with epoxide 3 having a reactive C3 carbon. Preferred epoxides are those that are enantiomerically enriched, such as the glycidyl tosylate 3 shown above that is condensed with phenol 2 for a time and temperature sufficient for reaction completion to provide epoxyaryl ether 4. See Example 1, Part 1 below for exemplary reaction conditions. The reagents 2 and 3 are typically reacted in a suitable solvent, e.g. dimethyl formamide, N-methyl pyrrolidinone and the like. Enantiomerically enriched epoxides suitable for condensation with an arylhydroxide are commercially available or can be readily prepared by known procedures. See, for instance, U.S. Pat. Nos. 4,946,974 and 5,332,843 to Sharpless et al. for preparation of optically active derivatives of glycidol.
The epoxyaryl ether 4 then is reacted with an active methylene group, such a diethyl or dimethyl malonate to provide butyrolactone 5. The exocyclic ester of 5 is then suitably cleaved, e.g. with reaction with magnesium chloride hexahydrate, to provide the aryllactone ether 6. See Example 1, Part 3 which follows for an exemplary reaction conditions. That lactone 6 is then reduced to the hydroxy-tetrahydrofuran 7. Suitable reducing agents include e.g. DIBAL-H and the like. See Example 1, Part 4, which follows. 
Schemes II and III exemplify further preferred methods of the invention for synthesis of alkynyl-substituted tetrahydrofuranaryl ethers. More specifically, the hydroxy substituent of tetrahydrofuran 7 is preferably protected, e.g. as an ether or ester. Thus, as depicted in Schemes II and III, the hydroxy moiety of 7 can be reacted with a suitable silyl reagent, e.g. to form the t-butyldimethylsilyl ether 8, or with reagent for esterification, e.g. an anhydride such as acetic anhydride to acetyl ester 11. See Example 1, Part 5 and Example 2, Part 1 for suitable reaction conditions for exemplary conditions.
The protected aryltetrahydrofuran ether 8 or 11 then can reacted to provide the alkynyl-substituted tetrahydrofuran 9 by treatment with a 1-alkyne in the presence of a strong base such an alkyllithium. Preferably the alkyne reagent contains a protected hydroxy moiety such as a silyl ether, e.g. a tetrahydropyranyl ether as depicted in the above Schemes. The hydroxy group can be readily deprotected after coupling of the alkynyl reagent to the tetrahydrofuran ring, e.g. by treatment with dilute acid. Typically, the alkyne reagent will contain a primary or secondary hydroxy moiety. 
Schemes IV and V above exemplify further convenient routes that can provide alkynyl-substituted tetrahydrofurans of Formula I. Thus, in Scheme IV, halo-substituted compound 12 can be reacted with an alkyne reagent as generally described above with respect to Schemes II and III to provide 9, which can be readily deprotected to provide the primary alcohol of compound 10. See generally Example 3 which follows for exemplary reaction conditions.
In Scheme V, hydroxytetrahydrofuran 7 (depicted as the lactol) is condensed with a sulfonic acid reagent to provide the sulfonic ester 8 which can be reacted with an alkyne reagent as generally described above to provide 9. Compound 10 is readily provided by treatment of the protected alcohol 9 with treatment with dilute acid. See Example 4 below.
Scheme VI below exemplifies a further preferred method of the invention that provides compounds of Formula I and involves cleavage of a bis-compound to provide high yields of compounds of Formula I. 
More specifically, as depicted above, trimethylene mannitol 16 is suitably prepared by condensation of mannitol 15 with formaldehyde in the presence of acid. The labile rings are cleaved and the resulting esters of 17 reduced to the primary and secondary alcohols of 18. The primary alcohols are protected, e.g. as an allyl or aryl sulfonic ester, to provide intermediate 19. The secondary hydroxyl groups of 19 then are functionalized by reaction with a trialkylorthoformate, e.g. a tri(C1-10alkyl)orthoformate such as triethylorthoformate, to provide 20. The protected primary alcohols of 20 are then converted to aryl ethers, preferably under basic conditions by reaction with an arylhydroxide compound such as a phenol to provide di-aryl ether 21. That aryl ether is then reacted in the presence of acid to cleave the methylene ethers to provide secondary hydroxyl groups of compound 22.
Compound 22 then undergoes oxidative cleavage by treatment with a suitable reagent such as Pb(OAc)4, and the resulting dialdehyde is functionalized to the acyclic xcex1,xcex2-unsaturated ester 23 such as by reaction with carboethoxymethylenetriphenyl phosphorane. Other xcex1,xcex2-unsaturated groups will for suitable for the alicyclic compound, e.g. xcex1,xcex2-unsaturated esters have 1 to about 12 carbon atoms, xcex1,xcex2-unsaturated acids, and other Michael-type acceptors. The carbon-carbon double bonds of 23 then are saturated, preferably by hydrogenation, and the resulting compound is cleaved and cyclized in the presence of acid to form the aryl ether 6. In one system, the saturated compound is refluxed in a suitable solvent such as an alcohol, ethanol, for a time sufficient to provide 6. See Example 5 which follows for exemplary reagents and reaction conditions. Compound 6 then can be further functionalized, e.g. as discussed above with respect to Schemes II and III. 
Scheme VII above exemplifies a further preferred method of the invention that provides compounds of Formula I and features multiple reactions that proceed as a single step without isolation of intermediates.
More specifically, as shown above aryl compound 2 is reacted with epoxide 24 that has a reactive C3 carbon to provide the arylepoxy ether 25. If the epoxide 24 is not enantiomerically enriched such as 3, the arylepoxy ether 25 may be resolved if desired such as by procedures generally depicted in Scheme VI above to provide optically active epoxide ethers 27 and 4. See Example 6, Parts 2-4 below for exemplary reagents and reaction conditions. That procedure generally entails formation of optically active aryldiol ether and arylepoxide ether 26 and 27 from the racemic arylepoxide 25 with an optically active reagent, preferably an optically active catalyst such as Jacobsen""s catalyst. See E. Jacobsen, Science, 277:936-938 (1997). The optically active diol 26 can be readily cyclized to the epoxide 4, for example by esterification (e.g. a sulfonic ester as shown exemplified by 28 above) of the primary hydroxyl group of the diol followed by epoxide formation under basic conditions (e.g. NaH).
An allyl halide is suitably reacted with the arylepoxide ether, suitably in the presence of Mg, catalytic amount of iodine and cuprous cyanide to provide aryl/alkene ether 29. The secondary hydroxy is suitably protected, e.g. as an ester, preferably as a sulfonic ester, to provide 30. An ester group is then suitably grafted to terminal carbon-carbon double bond to the xcex1,xcex2-unsaturated ester 31, and the ester reduced to the alcohol, typically by treatment with strong base such as DIBAL-H.
The alkene is then suitably oxidized to provide epoxy group of 33. The oxidation may be conducted to provide optically active epoxy carbons as generally shown in Scheme VI (compound 33) and conducted using suitable optically active reagent(s) such as an optically catalyst or other reagent. See Example 6, Part 9 for an exemplary procedure. The racemic epoxides also may be resolved, e.g. by chromatography using an optically active packing material. The glycidyl compound 33 is then converted to the epihalohydrin 34.
The epihalohydrin 34, in a single step, is converted to the alkynyltetrahydrofuran ether 35 upon treatment with a molar excess, preferably at least about a three molar excess of a strong base such as an alkyllithium reagent or sodium amide. BuLi is generally preferred, particularly n-BuLi.
While not being bound by theory, it is believed the single step reaction proceeds through the mechanism shown immediately below, where Ar is the same as defined for Formula I and Ms is mesyl (xe2x80x94S(O)2CH3): 
The alkynyl group of compound 35 can be further functionalized as desired, e.g. by reaction with ethylene oxide in the presence of base to afford the single enantiomer 10.
Compound 10 also can be further functionalized as desired. For example, to produce compound 1 as shown above, compound 10 can be reacted with N,O-bisphenoxycarbonyl hydroxylamine and triphenylphosphine and diisopropylazodicarboxylate, followed by treatment of resulting intermediate with NH3.
However, in a preferred aspect and as discussed above, the invention provides new routes to substituted hydroxy ureas. More particularly, a protected hydroxyurea (e.g., a compound of the formula NH2C(O)NHOR, where R is a hydroxy protecting group such as an alkyl, aryl or preferably aryalkyl ether such as an ether of an optionally substituted (phenyl)OCH2xe2x80x94) is reacted with a substituted alcohol compound such as 10 of Scheme II, preferably in the presence of suitable dehydrating agent(s) such as triphenyl phosphine and diethylazodicarboxylate (DEAD) to provide an amino ester, i.e. a moiety of the formula xe2x80x94NRC(O)OR1R where R is as defined immediately above and R1 is a non-hydrogen group such as aryl, particularly phenyl, alkyl, e.g. C1-10 alkyl, etc. That amino ester is then treated with ammonia and a Lewis acid such as boron trifluoride etherate and the like to provide a hydroxy urea.
Schemes VIII, IX and X exemplify preferred methods for synthesis of substituted oxepanes in accordance with the invention. 
Thus, as generally shown in Scheme VIII above, the halo benzyloxyalkane 41 is condensed with an arylether oxirane in the presence of an appropriate metal for a time and temperature sufficient for reaction completion to provide the arylbenzylether hydroalkane 42. The hydroxyl functionality of the arylether 42 is suitably protected especially as an ether such as methoxyethoxymethyl ether, methoxymethyl ether or tetrahydropyranyl ether and the like to provide the intermediate 43. The benzyl protection group of arylether 43 is removed under appropriate conditions such as hydrogenation using palladium on activated carbon. The resulting primary alcohol 44 is then oxidized to the corresponding aldehyde 45 using an appropriate oxidizing agent such as oxalyl chlorine with dimethyl sulfoxide in an appropriate solvent such as methylene chloride or chloroform, or a buffered solution of pyridinium dichromate in dry methylene chloride. 
The hydroxy group of 49 can be readily deprotected after coupling of the alkynyl reagent to the oxepane ring, e.g. by treatment with dilute acid such as a 1% HCl methanol solution to provide the alkynylhydroxy substituted oxepane 50 as shown in Scheme X. The arylether alkynylhydroxy oxepane 50 can be further functionalized as desired e.g. by amidation using a N,O-substituted hydroxylamine, preferably in the presence of dehydrating reagents such as triphenylphosphine and diisopropylazodicarboylate, followed by treatment of the resulting intermediate 51 with ammonia to yield the hydroxylamine oxepane 52. See the above discussion and Example 7, Parts 9 and 10 which follow for exemplary reaction conditions.
Synthetic methods of the invention also include preparation of compounds useful as intermediates to prepare 2,7-disubstituted tetrahydropyran compounds of the above Formula 1. 
Schemes XI, XII and XIII exemplify some preferred preparative methods of the invention for synthesis of alkynyl-substituted tetrahydropyrans.
Generally as shown is Scheme XI, the epoxy aryl ether 4, is reacted with a 1-alkyne reagent in the presence of a strong base such as butyl lithium and boron trifluoroetherate in THF to yield the alkyne 56. Preferably the alkyne reactant contains an ester moiety such as a methyl ester. The alkynyl functionality of arylether 56 is reduced under appropriate conditions such as hydrogenation using palladium on activated carbon as catalyst in an appropriate solvent such as methanol or ethanol to yield the alkane 57. Rearrangement with cyclization of the arylether methyl ester 57 is done by treatment with toluenesulfonic acid preferably in an appropriate solvent such as toluene to yield the tetrahydropyrrolinone 58. 
The aldehyde 58 is reduced, e.g. by reaction with dilsobutylaluminum hydride to yield the corresponding alcohol 58 as shown in Scheme XII. The arylether alcohol 59 and benzylsulfonic acid react in an appropriate solvent such as methylene chloride or chloroform in the presence of a drying agent such as calcium chloride to afford the cyclized arylether benzylsulfinic tetrahydropyran 60. The benzylsulfinic tetrahydropyran 60 can then react with a 1-alkyne in the presence of magnesium and isopropyl bromide to provide the alkynyl-substituted tetrahydropyran 61. Preferably the alkyne reactant contains a protected hydroxyl moiety such as tetrahydropyranyl ether or t-butyldimethylsilyl ether. It has been surprisingly found that reaction of the alkyne reagent with a mixture of a stereoisomers of 60 (i.e. racemic at phenylsulfinic-substituted ring carbon) proceeds stereoselectively to produce the trans compound 61. In fact, it has been found that the trans 61 compound can be the exclusive reaction product. The hydroxy group of 61 can be readily deprotected after coupling of the alkynyl reagent to the oxepane ring, e.g. by treatment with dilute acid such as a 1% HCl methanol solution to provide the alkynylhydroxy substituted tetrahydropyran 62. 
The arylether alkynylhydroxy tetrahydropyran 62 can be purified to yield the enantiomerically enriched disubstituted tetrahydropyran 63. The arylether alkynylhydroxy tetrahydropyran 63 further functionalized as desired by amidation using a N,O-substituted hydroxylamine, preferably in the presence of dehydrating reagents such as, triphenylphosphine and diisopropylazodicarboylate, followed by treatment of the resulting intermediate 64 with ammonia to yield the hydroxylamine tetrahydropyran 65.
Synthetic methods of the invention also include preparation of compounds useful as intermediates to prepare 2,7-disubstituted oxepane compounds of the above Formula II.
Scheme XIV below another preferred preparative method of the invention that employs a polyol (polyhydroxy) reagent. As depicted in the below Scheme, the entire reaction is stereoselective (i.e. no separate resolution step or procedure required), beginning with the optically active glyceraldehyde 1, which is commercially available. Other glyceraldehyde stereoisomers can be employed in the same manner as depicted in Scheme VIII to provide the corresponding distinct stereoisomer as the reaction scheme product.
In the following Schemes XIV through XVI, the compound numerals in the discussions of those Schemes are made in reference to the compound depicted in the particular Scheme, with the exception of compound 1, i.e. 2-(4-fluorophenoxymethyl)-5-(4-N-hydroxyureidyl-1-butynyl)-tetrahydrofuran.
As generally exemplified in Scheme XIV below, the chiral synthon (glyceraldehyde) is cyclized in the presence of base to the bis-dioxolane compound 2 which is then oxidized to the keto (aldehyde) dioxolane 3 and reacted with an appropriate Wittig reagent to provide the xcex1,xcex2-unsaturated ester 4. As referred to herein, unless specified otherwise, the term xe2x80x9cWittig reactionxe2x80x9d or xe2x80x9cWittig-type reactionxe2x80x9d designates any of the broad classes of alkene-formation reactions, typically involving ylide intermediates such as may be provided by phosphonate and phosphorane reagents. Additionally, as referred to herein, unless otherwise specified, to xe2x80x9cketoxe2x80x9d, xe2x80x9ccarbonylxe2x80x9d, or xe2x80x9ccarboxyxe2x80x9d or like term designate any functional group that includes a carbon-oxygen double bond (Cxe2x95x90O).
The carbon-carbon double bond produced by the Wittig reaction then can be saturated, e.g. hydrogenated in the presence of a suitable catalyst such as PtO2, and the ester reduced and then oxidized to provide aldehyde 7. Wittig reaction of the aldehyde moiety provides the xcex1,xcex2-unsaturated compound 9 which can be reduced to alcohol 9, and converted to the propargyl compound, e.g. via an epoxidized intermediate. More specifically, unsaturated alcohol 9 can be epoxidized to compound 10, suitably with an optically active oxidant and then elimination of the epihalohydrin derivative 11 in the presence of a suitable base e.g. LDA or other suitable agent to provide the propargyl compound 12. Additional, successive Wittig-type reactions with intervening carbon-carbon double bond saturation and aldehyde formation can be employed to prepare larger oxygen ring compounds. Thus, to prepare six-member oxygen alicyclic compounds of the invention, the sequence of steps shown in Scheme XIV below in the transformation of compound 3 to 7 would be repeated to compound 9a (which is compound 9 oxidized to the corresponding aldehyde). Similarly, to prepare seven member oxygen alicyclic compounds of the invention, the sequence of steps shown in Scheme XIV below in the transformation of compound 3 to 7 would be repeated two more times; to prepare eight member oxygen alicyclic compounds of the invention, the sequence of steps shown in Scheme XIV below in the transformation of compound 3 to 7 would be repeated three more times beyond that shown in the Scheme. Alternatively, or in combination with successive Wittig reactions, other Wittig reagents can be employed that provide for greater chain extension in a single step, e.g. Ph3Pxe2x95x90CHCH2CO2Et, Ph3Pxe2x95x90CHCH2CH2CO2Et, and the like, or corresponding Wadsworth-Emmons reagents.
Acidic opening of the dioxolane ring provides diol 14 and esterification (e.g. sulfonate ester such as a tosylate) provides the substituted tetrahydrofuran 16. The resulting hydroxy tetrahydrofuran can be functionalized as desired, e.g. esterification of the hydroxy followed by aryl substitution and functionalization of the alkynyl group provides compound 1, particularly 2S,5S-trans-(4-fluorophenoxymethyl)-5-(4-N-hydroxyureidyl-1-butynyl)-tetrahydrofuran. See, generally, Example 11 which follows for exemplary preferred reaction procedures. 
Scheme XV depicts a related approach to provide another stereoisomer of a substituted oxygen alicyclic compound. As shown in Scheme XV, L-ascorbic acid can be employed as a starting reagent to provide hydroxy dioxolane compound 19, which is oxidized; subjected to multiple Witting reactions; epoxidized; and an epihalohydrin intermediate reacted in the presence of base to form a proparoyl alcohol intermediate, which is converted to the optically active aryl-substituted alkyne tetrahydrofuran compounds 33 and 34. To produce larger ring compounds, additional, successive Wittig reactions can be carried out, as discussed above with respect to Scheme XIV. 
It should be appreciated that the unsubstituted alkyne produced through the routes of Schemes XIV and XV above is a versatile intermediate that can be further reacted to provide a wide range of moieties, including groups that can be detected, either upon in vitro or in vivo applications. For instance, the unsubstituted alkyne can be reacted with a group to provide radiolabeled and stable isotopic moieties, e.g. 125I, 3H, 32P, 99Tc, 14C, 13C, 15N or the like, which may be useful inter alia for mechanistic studies.
Scheme XVI below depicts highly efficient routes to oxygen alicyclic compounds of the invention. As shown in the Scheme, butynyl reagent 52 is treated with base, preferably a strong base such as an alkyl lithium e.g. butyl lithium, and then reacted with an unsaturated anhydride 53 to provide the keto alkynyl compound 54 with terminal alkene group. The alkene group is oxidized, e.g. via ozonolysis, and the keto-epoxide compound 55 reduced and cyclized in the presence of a suitable reducing agent, e.g. borane dimethyl sulfide. The resulting hydroxy tetrahydrofuran can be functionalized as desired, e.g. esterification of the hydroxy moiety followed by aryl substitution and functionalization of the alkynyl group provides 2-(4-fluorophenoxymethyl)-5-(4-N-hydroxyureidyl-1-butynyl)-tetrahydrofuran. See Example 12 which follows for exemplary preferred reaction conditions.
Larger ring compounds also can be prepared by this general route, e.g. by reaction of corresponding ring-extended compounds corresponding to compound 53 below. That is, to prepare oxygen alicyclic compounds having six ring members, the compound CH2xe2x95x90CH(CH2)3C(xe2x95x90O)OCOOEt can be employed in place of compound 53 in the below Scheme; to prepare oxygen alicyclic compounds having seven ring members, the compound CH2xe2x95x90CH(CH2)4C(xe2x95x90O)OCOOEt can be employed in place of compound 53 in the below Scheme; and to prepare oxygen alicyclic compounds having eight ring members, the compound CH2xe2x95x90CH(CH2)4C(xe2x95x90O)OCOOEt can be employed in place of compound 53 in the below Scheme. 
Schemes XVII and XVIII below depict routes to alicyclic compounds of the invention having one or preferably more hydroxy or alkoxy (e.g. C1-12 alkoxy, more preferably C1-8 or C1-6 alkoxy) substituents, preferably two hydroxy or alkoxy substituents on adjacent (vicinal) ring positions of the alicyclic compound. Thus, as shown in Scheme XVII below, mannose diacetonide 70 is converted to sulfide 72 followed by hydrolysis to provide 73. The alkylhydroxy ring substituent of 73 can be functionalized as desired, e.g. activation of a carbon such as by esterification (e.g. sulfonate, such as tosylate, mesylate, etc.) and nucleophilic substitution of the activated carbon, e.g. by an aryl nucleophile, particularly a carbocyclic aryl nucleophile such as a optionally substituted phenol. Other ring positions can be functionalized as desired, e.g. as shown in Scheme XVII, the sulfide group can be oxidized to the sulfone 74 to activate the ring carbon and that position substituted by a suitable reagent, e.g. a terminal alkyne, to provide compound 75. The vicinal alkoxy groups of compounds 75 and 76 can be readily converted to the corresponding vicinal di-hydroxy groups by acidic hydrolysis. Scheme XVIII shows alternate functionalization of the alicyclic compound. The di-alkoxy compounds 85 and 86 can be converted to the corresponding vicinal di-hydroxy compounds by acidic hydrolysis. 
Often, it will be preferable to use an optically active or enantiomerically enriched mixture of a chiral compound of the invention for a given therapeutic application. As used herein, the term xe2x80x9cenantiomerically enrichedxe2x80x9d refers to a compound mixture that is at least approximately 85% or 90%, and preferably a mixture of approximately at least about 95%, 97%, 98%, 99%, or 100% of a single enantiomer of the compound.
As discussed above, compounds of the invention are useful for numerous therapeutic applications. The compounds can be administered to a subject, particularly a mammal such as a human, in need of treatment, by a variety of routes. For example, the compound can be administered orally, parenterally, intravenously, intradermally, subcutaneously, or topically. For example, for parenteral application, particularly suitable are solutions, preferably oily or aqueous solutions as well as suspensions, emulsions, or implants, including suppositories. Ampules are convenient unit dosages. For enteral application, particularly suitable are tablets, degrees or capsules e.g. having talc and/or carbohydrate carrier binder or the like, the carrier suitably being lactose and/or corn starch and/or potato starch.
The active compound may be administered to a subject as a pharmaceutically active salt, e.g. salts formed by addition of an inorganic acid such as hydrochloric acid, hydrobromic acid, phosphoric acid, etc., or an organic acid such as acetic acid, oxalic acid, tartaric acid, succinic acid, etc. Base addition salts also can be formulated if an appropriate acidic group is present on the compound. For example, suitable base addition salts include those formed by addition of metal cations such as zinc, calcium, etc., or salts formed by addition of ammonium, tetraethylammonium, etc. Suitable dosages for a given therapy can be readily determined by the medical practitioner based on standard dosing protocols. See also U.S. Pat. No. 5,703,093.